Nucleic acid derivatives such as oligonucleotides are substances useful for variety of uses, such as the use for therapeutic and prophylactic treatments and diagnosis of diseases as well as the use as nanomaterials. However, natural DNAs and RNAs have a problem that they are unstable against nucleases (refer to, for example, Wada, T., “Frontier of Development of Nucleic acid Medicine”, Chapter 1 Development of nucleic acid medicines, 3.3 Chemical synthesis of phosphorus atom-modified nucleic acids, pp.67-'75, CMC Publication, published on February, 2009 and the like). Meanwhile, it has been elucidated by in vivo researches that properties of antisense nucleic acids, such as sequence-specific binding ability for binding with complementary RNAs and stability against nucleases, are influenced by three-dimensional configuration of phosphorus atom in nucleic acid derivatives. Therefore, it is desired to provide a method for preparing a nucleic acid derivative having stability against decomposition by a nuclease and having affinity for a complementary DNA or RNA sequence in vivo or in vitro by controlling three-dimensional configuration of phosphorus atom. It is also desired to provide a means that enables easy preparation of such nucleic acid derivatives by the solid phase method or the liquid phase method, and various chemical modifications of nucleic acid derivatives at sugar or base moieties.
From the aforementioned points of view, nucleic acid derivatives having a phosphorus atom modified with a sulfur atom or boron atom have been focused, and several techniques for controlling the three-dimensional configuration of phosphorus atom in the manufacture of such derivatives have been provided. For example, Japanese Patent Unexamined Publication (KOKAI) No. 2005-89441 discloses a method for preparing a phosphorus atom-modified nucleic acid derivative of high stereoregularity, of which process utilizes a compound represented by the general formula (3) as an activator, and proceeds via a compound represented by the general formula (13) as a reaction intermediate (oxazaphospholidine method). In this method, an optically active nucleoside 3′-phosphoramidite represented by the general formula (1) is prepared, and reacted as a starting material (monomer) with a nucleoside together with the activator represented by the general formula (3), and the resultant is appropriately protected, and then reacted with an electrophilic reagent to prepare the compound represented by the general formula (13). However, this method has problems that the yield of the synthesis of the monomer is low, the monomer is chemically unstable, and thus industrial application thereof is considered to be difficult.
In International Patent Publication WO2010/064146, a method for preparing a phosphorus atom-modified nucleic acid derivative is proposed, which uses an auxiliary group for asymmetric induction (henceforth also referred to as “chiral auxiliary” in the specification). This publication discloses a method for preparing a phosphorus atom-modified nucleic acid derivative in a high asymmetric yield, in which a compound represented by Formula 3 is reacted with a phosphorus atom of a nucleic acid derivative to prepare a compound of Formula 4 wherein D is a group represented by Formula A (residue of the compound of Formula 3) or a compound represented by Formula 5, and then the chiral auxiliary is removed. The outline of this method is shown in the following scheme. This method, utilizing the chiral auxiliary, can use an achiral H-phosphonate monoester as a starting material, which is chemically stable and can be synthesized in a large scale, and can perform the condensation reaction by forming the optically active monomer within the reaction system without isolation and purification thereof. Therefore, the method is more industrially advantageous compared with the method disclosed in Japanese Patent Unexamined Publication (KOKAI) No. 2005-89441.

The compound used for introducing the chiral auxiliary in the method described above is a compound having the following structure (compound represented by Formula 3 in the aforementioned publication).
[In the formula, W1 and W2 independently represent —NG5—, —O—, or —S—, and G1, G2, G3, G4, and G5 independently represent hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heteroaryl group, or an aryl group, or two of G1, G2, G3 G4, and G5 bind together to become G6 and represent a saturated or partially unsaturated or unsaturated monocyclic, polycyclic, condensed ring or non-condensed ring hydrocarbon ring group or heteroatom-containing ring group comprising up to about 20 members (provided that at most four of G1, G2, G3, G4, and G5 can become G6)].
However, this publication discloses only the following four kinds of compounds as the compound of Formula 3, and all of these are compounds wherein W1 is —NG5—, and G4 and G5 bind together to form a ring system according to the aforementioned definitions. In this method, the chiral auxiliary introduced by using the compound represented by Formula O or Formula P is removed under a basic condition, and the chiral auxiliary introduced by using the compound represented by Formula Q or Formula R is removed under an acidic condition. In the aforementioned scheme, Route A represents a synthetic method in which the chiral auxiliary is removed under a basic condition in the final step of the condensation cycle for chain length extension, and Route B represents a synthetic method in which the chiral auxiliary is removed under an acidic condition in each condensation cycle for chain length extension.
